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A multiplexed, single-cell sequencing screen identifies compounds that increase neurogenic reprogramming of mammalian Muller glia.

ABSTRACT: A multiplexed, single-cell sequencing screen identifies compounds that increase neurogenic reprogramming of mammalian Muller glia.

PROVIDER: PRJNA1000634 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25471600.fastq.gz	Fastqsanger.gz
	SRR25471601.fastq.gz	Fastqsanger.gz
	SRR25471602.fastq.gz	Fastqsanger.gz
	SRR25471603.fastq.gz	Fastqsanger.gz
	SRR25471604.fastq.gz	Fastqsanger.gz

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A multiplexed, single-cell sequencing screen identifies compounds that increase neurogenic reprogramming of mammalian Muller glia.

Project description:Neurodegeneration in the retina of mammals causes permanent loss of vision, due to their lack of regeneration. Some non-mammalian vertebrates show robust regeneration, via the Muller glia (MG), and we have recently made significant progress in stimulating adult mouse MG to regenerate functional neurons by transgenic expression of the proneural transcription factor Ascl1. While these results showed that MG can serve as an endogenous source of neuronal replacement, the efficacy of this process is limited. We designed a small molecule screen using sci-Plex, a method to multiplex up to thousands of single nucleus RNA-seq conditions into a single experiment, to screen a library of 92 compounds, identified, and validated two that promote neurogenesis in vivo. Our results demonstrate that high-throughput single-cell molecular profiling can substantially improve the discovery process for molecules and pathways that can stimulate neural regeneration and further demonstrate the potential for this approach to restore vision in patients with retinal disease.

2024-01-15 | GSE239731 | GEO

RNA-seq to investigate the adult mouse Muller glia transcriptome

Project description:These data serve as a reference transcriptomic profile for adult mouse retinal Muller glia. Retinas were dissociated into single cell suspensions and sorted into two fractions: a Muller glia-enriched fraction on the basis of Muller glia-specific tdTomato expression and a second fraction containing the remaining retinal cells that were tdTomato-negative. Both fractions were sequenced.

2020-08-02 | E-MTAB-7058 | biostudies-arrayexpress

Comparative transcriptomic and epigenomic analysis identifies key regulators of injury response and neurogenic competence in retinal glia

Project description:Injury induces retinal Muller glia of non-mammalian, but not mammalian, vertebrates to generate neurons. To identify gene regulatory networks that control neurogenic competence in retinal glia, we used bulk and single-cell RNA-seq and ATAC-seq analysis to comprehensively profile gene expression and chromatin conformation in Muller glia from zebrafish, chick and mice. This was conducted during glial development, following inner and outer retinal injury, as well as following treatment with extrinsic factors that induce glial reprogramming. Integration of these data, together with functional analysis of candidate genes, identified evolutionarily conserved and species-specific gene regulatory networks controlling glial quiescence, gliosis, and neurogenic competence. In zebrafish and chick, transition from quiescence to gliosis is a necessary stage in acquisition of neurogenic competence, while in mice a dedicated network suppresses this transition and rapidly restores quiescence. These findings may help guide the design of cell-based therapies aimed at restoring retinal neurons lost to disease.

2020-05-01 | GSE135406 | GEO

ASCL1 induces neurogenesis in human Muller glia

Project description:In mammals, loss of retinal cells due to disease or trauma is an irreversible process which can lead to blindness. Interestingly, regeneration of retinal neurons is a well-established process in some non-mammalian vertebrates and is driven by the Muller glia (MG), which are able to re-enter the cell cycle and reprogram into neurogenic progenitors upon retinal injury or disease. Progress has been made to restore this mechanism in mammals to promote retinal regeneration: MG can be stimulated to generate new neurons in vivo in the adult mouse retina after the over-expression of the pro-neural transcription factor Ascl1. In this study, we applied the same strategy to reprogram human MG derived from fetal retina and retinal organoids into neurons. Combining scRNA-seq, scATAC-seq, Immunofluorescence, and electrophysiology we demonstrate that human MG can be reprogrammed into neurogenic cells in vitro.

2023-10-30 | GSE246169 | GEO

Differential expression in Muller glia of injured zebrafish in a mycb-/- context

Project description:This experiment studies retinal regeneration using a zebrafish model with a focus on Muller glia reprogramming.

2024-05-10 | GSE249116 | GEO

Differential expression in Muller glia of injured zebrafish in a mych-/- context

Project description:This experiment studies retinal regeneration using a zebrafish model with a focus on Muller glia reprogramming.

2024-05-10 | GSE249115 | GEO

Oct4 overexpression and suppression of Notch signaling synergistically induce neurogenic competence in mammalian Muller glia.

Project description:Oct4 overexpression and suppression of Notch signaling synergistically induce neurogenic competence in mammalian Muller glia.

| PRJNA1162090 | ENA

ASCL1 induces neurogenesis in human Muller glia

Project description:ASCL1 induces neurogenesis in human Muller glia

| PRJNA1031951 | ENA

Expression profiling of Ascl1-reprogrammed P12 Müller glia compared with freshly dissociated progenitors and Müller glia

Project description:Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia cells (MG) that activate the proneural factor Achaete-scute homolog 1 (Ascl1/Mash1) and de-differentiate into progenitors cells. In contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether Ascl1 could restore a neurogenic potential to mammalian MG, we over-expressed Ascl1 in dissociated mouse MG cultures and intact retinal explants. Ascl1-infected MG upregulate retinal progenitor-specific genes, while downregulating glial genes. Furthermore, Ascl1 remodeled the chromatin at its targets from a repressive to active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers, and displayed neuron-like physiological responses. These results indicate that a single transcription factor, Ascl1, can produce a neurogenic state in mature Muller glia. Expresssion profiling was used to determine the genes that were changed after Ascl1 infection of P12 cultured Müller glia compared with those present in P0 progenitors and P7-P21 Müller glia Retinas were dissociated and FAC-sorted from Hes5-GFP mice at P0, P7, P10, P14 or P21 and submitted for profiling. WT Retinas were dissociated at P12, grown for 1 week in culture, and infected with lentiviruses expressing Ascl1 or GFP for four days. Total RNA was extracted and submitted for profiling.

2013-04-06 | E-GEOD-45835 | biostudies-arrayexpress

Efficient stimulation of retinal regeneration from Muller glia in adult mice using combinations of proneural bHLH transcription factors.

Project description:Regenerative neuroscience aims to stimulate endogenous repair mechanisms in the nervous system to replace neurons that have been lost from degenerative diseases or trauma. In the retina, many non-mammalian vertebrate species spontaneously regenerate retinal neurons from glial cells, through an injury-induced reprogramming of the cells to a retinal progenitor state. Recently, we have reported that engineering mouse Muller glia to express a retinal progenitor gene, the proneural transcription factor, Ascl1, is sufficient to stimulate neurogenesis in the glia to generate functional neurons. However, this process is inefficient and only a third of the Ascl1-expressing glia generate new neurons. Here we test whether proneural transcription factors of the Atoh1/7 class can further promote the neurogenic capacity of MG. We report that the combination of Ascl1:Atoh1 is remarkably efficient at stimulating neurogenesis (>80% expressing cells), even in the absence of retinal injury or TSA. We use electrophysiology and scRNA-seq to demonstrate that Ascl1:Atoh1 generates a diversity of retinal neuron types with the majority expressing characteristics of retinal ganglion cells. Overall, our results provide a proof-of-principle that transcription factors that are normally sequentially active in cell fate specification, can when combined, substantially improve glial reprogramming to neurons and expand the repertoire of cell fates that can be regenerated in the adult mouse retina. The ability to stimulate the neurogenic potential of glia in adult mice with high efficiency is a key step towards translation of this approach to repair the central nervous system.

2021-10-19 | GSE184286 | GEO

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